I= SYNTHESIS AND BIOASSAY OF NEUROTENSIN MIMETICS AND ANTHRAQUINONES, METHODOLOGY FOR THE SYNTHESIS OF CHIRAL DITHIOACETALS
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Title of Thesis
SYNTHESIS AND BIOASSAY OF NEUROTENSIN MIMETICS AND ANTHRAQUINONES, METHODOLOGY FOR THE SYNTHESIS OF CHIRAL DITHIOACETALS

Author(s)
Fazal Naeem
Institute/University/Department Details
Department of Chemistry/ Quaid-i-Azam University, Islamabad
Session
2004
Subject
Organic Chemistry
Number of Pages
219
Keywords (Extracted from title, table of contents and abstract of thesis)
neurotensin, neurotensin mimetics, non-peptidic mimetics, anthraquinones, dithioacetals, oxathioacetals, schizophrenia, parkinson, alzheimer, trideca peptide, anthracenes, cytotoxic activity

Abstract
The research work reported in this thesis is divided into three parts. Each part describes the historic background the significance the experimental details and results and discussion that encompasses characterization of each type of reaction and bioassay of the final products. Part-I is related to the synthesis of mimetics of neurotensin, NT (8-13) and their binding affinity to the NT receptor. The synthesis and biostudies of mimetics of NT are directed to design a drug for psychiatric diseases like schizophrenia, parkinson and alzheimer. NT is linear trideca peptide (pGlu-Leu-Tyr-Glu-Asn-Lys-Pro-Arg-Arg-Pro-Tyr-lle-Leu) present in brain and has a wide range of central and peripheral pharmacological effects. NT and NT (8-13), being peptides cannot be used as drugs because of their susceptibility to enzymatic degradation, difficulty in crossing the blood brain barrier and poor bioavailability. Development of non peptidic analogs has therefore, been a continuing interest. In this effort to develop full or partial non peptidic NT mimetics, two compounds, (1) and (2) were synthesized following the multiple template approach (MT A). Compound (2), due to its unique properties over compound (1) was selected as the lead compound for the synthesis of NT mimetics. Some of these mimetics were found to posses different degrees of affinities to NT receptor.

During the present work three NT (8-13) mimetics (52), (74) and (76) were synthesized. This synthesis involved the use of pyrrole -2-carboxylic acid, 3-hydroxybenzaldehyde and 4-methoxy-3-hydroxybenzaldehyde in different synthetic schemes. The bioassays of the three synthesized mimetics (52), (74) and (76) were performed at the Mayo Clinic, Jacksonville Florida, USA under the supervision of Pro£ Dr. E. Richelson. All the intermediate and final products were fully characterized from their spectroscopic data.

Part-II of the thesis is concerned with the synthesis and bioactivities of some naturally occurring anthraquinones, These natural anthraquinones have often been reported to be biologically active. They include anthracycline antibiotics and their analogues which are used in chemotherapy of solid tumors of breast, lung, bladder and ovary. As a result of the present work, four naturally occurring anthraquinones (97-100) were successfully synthesized by an easy and highly selective general method, starting from the relatively inexpensive commercially available starting materials i.e. 1,8-dihydroxy-9,10-anthraquinone (101) and its regioisomer 1,5-dihydroxy-10- anthraquinone (102). The sequence of reactions consist of the protection of hydroxyl groups by MOM chloridet reduction of anthraquinone to corresponding anthracene by metalation /stannylationt iodination and coupling of the methyl groups, selectively at ortho position of the antyhracene rings using Nigishi methodology. The regeneration of the anthraquinones from anthracenes by specific oxidizing reagent bis silver permanganate followed by deprotection reaction yielded isochrysophanol (97) and isozyganein (98). In the synthesis of the other two anthraquinones, w-hydroxy isochrysophanol (99) and morindaparvin (100), the intermediate stannanes were routed to esters. Then the corresponding esters were reduced to alcohols using di-isobutyl aluminum hydride (DiBAL). The crude alcohols were protected using ethyl vinyl ether (EVE). Anthraquinones were regenerated from anthracenes and the deprotection process yielded the desired anthraquinones ",-hydroxyl isochfygophanol (99) and morindaparvin (l00). Each of the four synthesized compound was screened out for in-vitro antibacterial activity which showed moderate activity against these bacteria. The in-vitro cytotoxic bioassay of the synthesized compounds showed no cytotoxic activity. An antioxidative assay of compounds revealed that they act as a weak 1-1-diphenyl-2-picrylhydrazyl (DPPH) radical scavengers.

Part III of the thesis describes the cost effective synthesis of dithioacetals and oxathioacetals. Some enantiomerically pure dithioacetals and oxathioacetals were synthesized with the same method in order to study asymmetric induction reaction in future. All the synthesized dithioacetals and oxathioacetals were fully characterized from their spectral data and optical rotations. The synthesized dithioacetals and oxathioacetals were also screened out for in-vitro antibacterial and antifungal activity. They showed variable activity. The in-vitro cytotoxic bioassay (lethality test) of compounds using Mc-Laughlin brine shrimp was also performed. All the compounds tested were nontoxic except menthoxy methyl phenyl sulphide (135) which showed positive lethality.

Download Full Thesis
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S. No. Chapter Title of the Chapters Page Size (KB)
1 0 Contents 0
351.32 KB
2 1 Part I: Neurotensin Mimetics 1
310.79 KB
3 2 Results And Discussion 23
730.14 KB
4 3 Experimental 58
601.09 KB
5 4 Part II: Anthraquinones 86
180.94 KB
6 5 Results And Discussion 96
591.82 KB
7 6 Reagents 119
333.39 KB
8 7 Part III: Dithioacetals And Oxathioacetals 137
113.94 KB
9 8 Results And Discussion 143
755.09 KB
10 9 Experimental 173
397.83 KB